Heart failure is a primary cause of morbidity and mortality worldwide. The onset and clinical course of heart failure is dictated by a complex interplay of environmental and hereditary factors. Population studies have identified a number of genetic links to heart disease, however, many of the variants are non-coding in nature, and our ability to make sense of these associations has been hampered by our limited knowledge of the vast genomic regulatory system that controls circulatory system gene expression. Recently, microRNAs (miRs) have emerged as key gene regulators in cardiac biology and disease. These small non-coding RNAs are loaded into Argonaute (Ago) proteins to direct post-transcriptional gene suppression by base-pairing with target transcripts, and notably, genetic variants disrupting this regulation have been linked to disease. To understand miR functions and their interface with genetics and heart disease, identifying their targets sites is paramount. Unfortunately, there is a paucity of empirical miR targeting data in human cardiac tissues, slowing the translational impact of the many investigations of disease-relevant miRs. To bolster these efforts, our overarching goal is to define miR targeting events and their biological-relevance in human hearts and to understand the clinical significance of genetic variants that alter cardiac miR functions. In this grant, we will address limitations in identifying miR binding sites important to the pathogenesis and genetic basis of heart disease by employing high-throughput techniques to globally profile miR-target interactions in human cardiac tissues. The central hypothesis is two-fold: 1) that miR-target interactions are significantly rewired in failing human hearts, and 2) that genetic variations (e.g. SNPs) perturbing these interactions will impact the clinical course of heart disease. In Aim 1, we will fill significant knowledge gaps regarding the mechanistic targets of cardiac miRs by generating transcriptome-wide maps of miR binding sites in ?normal? non-failing and failing human heart tissues. The resulting data will point to translationally-relevant SNPs that may modulate cardiomyopathy- and arrhythmia-related miR-target interactions (tested in Aim 2), having the potential to reveal new genetic modifiers that contribute to disease heterogeneity. Finally, in Aim 3, we will determine if SNPs of this nature are linked to clinical outcomes (e.g. survival and fatal arrhythmias) in multiple heart failure patient cohorts, discovering novel inherited risk factors that could impact patient management. In addition, we will push beyond basic genotype-phenotype links to gain insight into the underlying mechanisms by defining genotype-specific changes in global myocardial gene expression signatures. Overall, this work will 1) broadly advance our knowledge of cardiac miR functions, 2) facilitate the translation of genetic studies of heart disease towards novel pathogenic mechanisms and improvements in personalized medicine, and 3) support future efforts to extend the ?body map? of miR targeting to vascular tissues that are related to other prevalent multifactorial cardio-metabolic diseases with complex genetic underpinnings.